Cholecystokinin subtype 2 receptors (CCK2R) are overexpressed in several human
cancers, including medullary
thyroid carcinoma.
Gastrin and
cholecystokinin (CCK)
peptides that bind with high affinity and specificity to CCK2R can be used as carriers of radioactivity to CCK2R-expressing
tumor sites. Several
gastrin and CCK related
peptides have been proposed for diagnostic imaging and
radionuclide therapy of primary and metastatic CCK2R-positive human
tumors. Their clinical application has been restricted to a great extent by their fast in vivo degradation that eventually compromises
tumor uptake. This problem has been addressed by structural modifications of
gastrin and CCK motifs, which, however, often lead to suboptimal pharmacokinetic profiles. A major
enzyme implicated in the catabolism of
gastrin and CCK based
peptides is
neutral endopeptidase (NEP), which is widely distributed in the body. Coinjection of the NEP inhibitor
phosphoramidon (PA) with radiolabeled
gastrin and other
peptide analogs has been recently proposed as a new promising strategy to increase bioavailability and
tumor-localization of radiopeptides in
tumor sites. Specifically, co-administration of PA with the truncated
gastrin analog [(111)In-
DOTA]MG11 ([((111)In-
DOTA)DGlu(10)]
gastrin(10-17)) impressively enhanced the levels of intact radiopeptide in mouse circulation and has led to an 8-fold increase of CCK2R-positive
tumor uptake in SCID mice. This increased
tumor uptake, visualized also by SPECT/CT imaging, is expected to eventually translate into higher diagnostic sensitivity and improved therapeutic efficacy of radiolabeled
gastrin analogs in CCK2R-expressing
cancer patients.